Substituted porphyrins

ABSTRACT

The present invention relates, in general, to a method of modulating physiological and pathological processes and, in particular, to a method of modulating cellular levels of oxidants and thereby processes in which such oxidants are a participant. The invention also relates to compounds and compositions suitable for use in such methods.

TECHNICAL FIELD

[0001] The present invention relates, in general, to a method ofmodulating physiological and pathological processes and in particular toa method of modulating cellular levels of oxidants and thereby processesin which such oxidants are a participant. The invention also relates tocompounds and compositions suitable for use in such methods.

BACKGROUND

[0002] Oxidants are produced as part of the normal metabolism of allcells but also are an important component of the pathogenesis of manydisease processes. Reactive oxygen species, for example, are criticalelements of the pathogenesis of diseases of the lung, the cardiovascularsystem, the gastrointestinal system, the central nervous system andskeletal muscle. Oxygen free radicals also play a role in modulating theeffects of nitric oxide (NO•). In this context, they contribute to thepathogenesis of vascular disorders, inflammatory diseases and the agingprocess.

[0003] A critical balance of defensive enzymes against oxidants isrequired to maintain normal cell and organ function. Superoxidedismutases (SODs) are a family of metalloenzymes that catalyze theintra- and extracellular conversion of O₂ ⁻ into H₂O₂ plus O₂, andrepresent the first line of defense against the detrimental effects ofsuperoxide radicals. Mammals produce three distinct SODs. One is adimeric cooper- and zinc-containing enzyme (CuZn SOD) found in thecytosol of all cells. A second is a tetrameric manganese-containing SOD(Mn SOD) found within mitochondria, and the third is a tetrameric,glycosylated, copper- and zinc-containing enzyme (EC-SOD) found in theextracellular fluids and bound to the extracellular matrix. Severalother important antioxidant enzymes are known to exist within cells,including catalase and glutathione peroxidase. While extracellularfluids and the extracellular matrix contain only small amounts of theseenzymes, other extracellular antioxidants are also known to be present,including radical scavengers and inhibitors of lipid peroxidation, suchis ascorbic acid, uric acid, and α-tocopherol Halliwell et al. Arch.Biochem. Biophys. 230: (1990)).

[0004] The present invention relates generally to low molecular weightporphyrin compounds suitable for use in modulating intra- andextracellular processes in which superoxide radicals, or other oxidantssuch as hydrogen peroxide or peroxynitrite, are a participant. Thecompounds and methods of the invention find application in variousphysiologic and pathologic processes in which oxidative stress plays arole.

SUMMARY OF THE INVENTION

[0005] The present invention relates to a method of modulating intra- orextracellular levels of oxidants such as superoxide radicals, hydrogenperoxide, peroxynitrite, lipid peroxides, hydroxyl radicals and thiylradicals. More particularly, the invention relates to a method ofmodulating normal or pathological processes involving superoxideradicals, hydrogen peroxide, nitric oxide or peroxynitrite using lowmolecular weight antioxidants, and to methine (ie, meso) substitutedporphyrins suitable for use in such a method.

[0006] Objects and advantages of the present invention will be clearfrom the description that follows.

BRIEF DESCRIPTION OF THE DRAWING

[0007] FIGS. 1A-C show the structures of certain compounds of theinvention. The SOD activity values were determined using the method ofMcCord and Fridovich. J. Biol. Chem. 244:6049 (1969). The catalasevalues were determined using the method of Day et al, Arch. Biochem.Biophys. 347:256 (1997). The TBARS values were obtained as follows:

[0008] Homogenates

[0009] Frozen adult Sprague-Dawley rat brains, livers and mouse lungs(Pel-Freez. Rogers, AR) were homogenized with a polytron (Turrax T25.Germany) in 5 volumes of ice cold 50 mM potassium phosphate at pH 7.4.Homogenate protein concentration was determined with the Coomassie Plusprotein assay (Pierce, Rockford, Ill.) using bovine serum albumin as astandard. The homogenate volume was adjusted with buffer to give a finalprotein concentration of 10 mg/ml and frozen as aliquots at −80° C.

[0010] Oxidation of Homogenates

[0011] Microfuge tubes (1.5 ml) containing 0.2 ml of homogenate (0.2 mgprotein) and various concentrations of antioxidant were incubated at 37°C. for 15 minutes. Oxidation of the rat brain homogenate was initiatedby the addition of 0.1 ml of a freshly prepared stock anaerobic solutioncontaining ferrous chloride (0.25 mM) and ascorbate (1 mM). Samples wereplaced in a shaking water bath at 37° C. for 30 minutes (final volume 1ml). The reactions were stopped by the addition of 0.1 μL of a stockbutylated hydroxytoluene (60 mM) solution in ethanol.

[0012] Lipid Peroxidation Measurement

[0013] The concentration of thiobarbituric acid reactive species (TBARS)in rat brain homogenates was used as a index of lipid peroxidation.Malondialdehyde standards were obtained by adding 8.2 μL of1.1.3.3-tetramethoxypropane in 10 ml of 0.01 N HCl and mixing for 10minutes at room temperature. This stock was further diluted in water togive standards that ranged from 0.25 to 25 μM. Samples or standards (200μL) were acidified with 200 μL of 0.2 M stock of phosphoric acid in 1.5ml locking microfuge tubes. The color reaction was initiated by theaddition of 25 μL of a stock thiobarbituric acid solution (0.11 M) thatwas mixed and then placed in a 90° C. heating block for 30 minutes.TBARS were extracted with 0.5 ml of n-butanol by vortexing for 3 minutesand chilling on ice for 1 minute. The samples were then centrifuged at12.000x g for 3 minutes and a 150 μL aliquot of the n-butanol phase wasplaced in each well of a 96-well plate and read at 535 nm in a Thermomaxplatereader (Molecular Devices. Sunnydale, Calif.) at 25° C. Sampleabsorbances were converted to MDA equivalences (μM) by extrapolationfrom the MDA standard curve. None of the antioxidants at concentrationsemployed in these studies affected the reaction of MDA standards withthiobarbituric acid.

[0014] Statistical Analyses

[0015] Data were presented as their means±SE. The inhibitoryconcentration of antioxidants that decreased the degree of lipidperoxidation by 50% (IC₅₀) and respective 95% confidence intervals (CI)were determined by fitting a sigmoidal curve with variable slope to thedata (Prizm. GraphPad. San Diego, Calif.). (See also Braughler et al. J.Biol. Chem. 262:10438 (1987); Kikugawa et al. Anal. Biochem. 202:249(1992).)

[0016]FIG. 2 shows the data obtained from a study involving treatment ofbronchopulmonary dysplasia using Aeol-V.

DETAILED DESCRIPTION OF THE INVENTION

[0017] The present invention relates to methods of protecting againstthe deleterious effects of oxidants, particularly, superoxide radicals,hydrogen peroxide and peroxynitrite, and to methods of preventing andtreating diseases and disorders that involve or result from oxidantstress. The invention also relates methods of modulating biologicalprocesses involving oxidants, including superoxide radicals, hydrogenperoxide, nitric oxide and peroxynitrite. The invention further relatesto compounds and compositions, including low molecular weightantioxidants (eg mimetics of scavengers of reactive oxygen species,including mimetics of SODs, catalases and peroxidases) and formulationsthereof, suitable for use in such methods.

[0018] Mimetics of scavengers of reactive oxygen species appropriate foruse in the present methods include methine (ie meso) substitutedporphines, or pharmaceutically acceptable salts thereof (eg chloride orbromide salts). The invention includes both metal-free and metal-boundporphines. In the case of metal-bound porphines, manganic derivatives ofmethine (meso) substituted porphines are preferred, however, metalsother than manganese such as iron (II or III), copper (I or II), cobalt(II or III), or nickel (I or II), can also be used. It will beappreciated that the meal selected can have various valence states, forexample. manganese II-III or V can be used. Zinc (II) can also be usedeven though it does not undergo a valence change and therefore will notdirectly scavenge superoxide. The choice of the metal can affectselectivity of the oxygen species that is scavenged. Iron-boundporphines, for example, can be used to scavenge NO• whilemanganese-bound porphines scavenge NO• less well.

[0019] The mimetics of the present invention are of the Formula 1:

[0020] or pharmaceutically acceptable salt thereof

[0021] wherein

[0022] R₁ and R₃ are the same and are:

[0023] R₂ and R₄ are the same and are:

[0024] Y is halogen or —CO₂X,

[0025] each X is the same or different and is an alkyl and each R₅ isthe same or different (preferably the same) and is H or alkyl.

[0026] Preferably, R₁ and R₃ are the same and are:

[0027] R₂ and R₄ are the same and are:

[0028] Y is —F or —CO₂X

[0029] each X is the same or different and is an alkyl (preferably, C₁₋₄alkyl. e.g., methyl or ethyl) and each R

is the same or different (preferably the same) and is H or alkyl(preferably, C₁₋₄ alkyl, e.a. —CH₃ or —CH₂CH₃).

[0030] Most preferably, R₁, R₂, R₃ and R₄ are the same and are

[0031] or

[0032] and each X is the same or different and is C₁₋₄ alkyl,advantageously, methyl or ethyl, particularly, methyl.

[0033] Specific examples of mimetics of the invention are shown in FIG.1, together with activity data.

[0034] In addition to the methine (meso) substituents described above,one or more of the pyrrole rings of the porphyrin of Formula I can besubstituted at any or all beta carbons. ie: 2, 7, 8, 12, 13, 17 or 18.Such substituents, designated P. can be hydrogen or an electronwithdrawing group, for example, each P can, independently, be a NO₂group, a halogen (eg Cl, Br or F), a nitrile group, a vinyl group, or aformyl group. Such substituents alter the redox potential of theporphyrin and thus enhance its ability to scavenge oxygen radicals. Forexample, there can be 1, 2, 3, 4, 5, 6, 7, or 8 halogen (eg Br)substituents (preferably, 1-4), the remaining P's advantageously beinghydrogen. When P is formyl, it is preferred that there not be more than2 (on non-adjacent carbons), more preferably, 1 the remaining P'spreferably being hydrogen. When P is NO₂, it is preferred that there notbe more than 4 (on non-adjacent carbons), more preferably, 1 or 2, theremaining P's being hydrogen.

[0035] Where isomers are possible, all such isomers of the hereindescribed mimetics are within the scope of the invention.

[0036] Mimetics preferred for use in the present methods can be selectedby assaying for SOD, catalase and/or peroxidase activity. Mimetics canalso be screened for their ability to inhibit lipid peroxidation orscavenge ONOO⁻ (as determined by the method of Szabo et al, FEBS Lett.381:82 (1996)).

[0037] SOD activity can be monitored in the presence and absence of EDTAusing the method of McCord and Fridovich (J. Biol. Chem. 244:6049(1969)). The efficacy of a mimetic can also be determined by measuringthe effect of the mimetic on the aerobic growth of a SOD null E. colistrain versus a parent strain. Specifically, parental E. coli (AB1157)and SOD null E. coli (J1132) can be grown in M9 medium containing 0.2%casamino acids and 0.2% glucose at pH 7.0 and 37° C.: growth can bemonitored in terms of turbidity followed at 700 nm. This assay can bemade more selective for SOD mimetics by omitting the branched chain,aromatic and sulphur-containing amino acids from the medium (glucoseminimal medium (M9), plus 5 essential amino acids).

[0038] Efficacy of active mimetics can also be assessed by determiningtheir ability to protect mammalian cells against methylvinologen(paraquat)-induced toxicity. Specifically, rat L2 cells grown asdescribed below and seeded into 24 well dishes can be pre-incubated withvarious concentrations of the SOD mimetic and then incubated with aconcentration of methylviologen previously shown to produce an LC₇₅ incontrol L2 cells. Efficacy of the mimetic can be correlated with adecrease in the methylviologen-induced LDH release (St. Clair et al.FEBS Lett. 293:199 (1991)).

[0039] The efficacy of SOD mimetics can be tested in vivo with mouseand/or rat models using both aerosol administration and parenteralinjection. For example, male Balb/c mice can be randomized into 4 groupsof 8 mice each to form a standard 2×2 contingency statistical model.Animals can be treated with either paraquat (40 mg/kg, ip) or saline andtreated with SOD mimetic or vehicle control. Lung injury can be assessed48 hours after paraquat treatment by analysis of bronchoalveolar lavagefluid (BALF) damage parameters (LDH, protein and

% PMN) as previously described (Hampson et al, Tox. Appl. Pharm. 98:206(1989); Day et al, J. Pharm. Methods 24:1 (1990)). Lungs from 2 mice ofeach group can be instillation-fixed with 4% paraformaldehyde andprocessed for histopathology at the light microscopic level.

[0040] Catalase activity can be monitored by measuring absorbance at 240nm in the presence of hydrogen peroxide (see Beers and Sizer, J. Biol.Chem. 195:133 (1952)) or by measuring oxygen evolution with a Clarkoxygen electrode (Del Rio et al. Anal. Biochem. 80:409 (1977)).

[0041] Peroxidase activity can be measured spectrophotometrically aspreviously described by Putter and Becker: Peroxidases. In: Methods ofEnzymatic Analysis. H. U. Bergmeyer (ed.). Verlag Chemie. Weinheim, pp.286-292 (1983). Aconitase activity can be measured as described byGardner and Fridovich (J. Biol. Chem. 266: 19328 (1991)). The selective,reversible and SOD-sensitive inactivation of aconitase by known O₂

generators can be used as a marker of intercellular O₂

generation. Thus, suitable mimetics can be selected by assaying for theability to protect aconitase activity.

[0042] The ability of mimetics to inhibit lipid peroxidation can beassessed as described by Ohkawa et al (Anal. Biochem. 95:351 (1979)) andYue et al (J. Pharmacol. Exp. Ther. 263:92 (1992)). Iron and ascorbatecan be used to initiate lipid peroxidation in tissue homogenates and theformation of thiobarbituric acid reactive species (TBARS) measured.

[0043] Active mimetics can be tested for toxicity in mammalian cellculture by measuring lactate dehydrogenase (LDH) release. Specifically,rat L2 cells (a lung Type II like cell (Kaighn and Douglas, J. CellBiol. 59:160a (1973)) can be grown in Ham's F-12 medium with 10% fetalcalf serum supplement at pH 7.4 and 37° C.; cells can be seeded at equaldensities in 24 well culture dishes and grown to approximately 90%confluence; SOD mimetics can be added to the cells at log doses (egmicromolar does in minimal essential medium (MEM) and incubated for 24hours. Toxicity can be assessed by morphology and by measuring therelease of the cytosolic injury marker, LDH (eg on a thermokinetic platereader), as described by Vassault (In: Methods of Enzymatic Analysis,Bergmeyer (ed) pp. 118-26 (1983); oxidation of NADH is measured at 340nm).

[0044] The mimetics of the present invention are suitable for use in avariety of methods. The compounds of Formula I, particularly the metalbound forms (advantageously, the manganese bound forms), arecharacterized by the ability to inhibit lipid peroxidation. Accordingly,these compounds are preferred for use in the treatment of diseases ordisorders associated with elevated levels of lipid peroxidation. Thecompounds are further preferred for use in the treatment of diseases ordisorders mediated by oxidative stress. Inflammatory diseases areexamples, including asthma, inflammatory bowel disease, arthritis andvasculitis.

[0045] The compounds of the invention (advantageously, metal bound formsthereof) can also be used in methods designed to regulate NO• levels bytargeting the above-described porphines to strategic locations. NO• isan intercellular signal and, as such, NO• must traverse theextracellular matrix to exert its effects. NO•, however, is highlysensitive to inactivation mediated by O₂

present in the extracellular spaces. The methine (meso) substitutedporphyrins of the invention can increase bioavalability of NO• bypreventing its degradation by O₂

.

[0046] The present invention relates, in a further specific embodiment,to a method of inhibiting production of superoxide radicals. In thisembodiment, the mimetics of the invention (particularly metal boundforms thereof) are used to inhibit oxidases, such as xanthine oxidase,that are responsible for production of superoxide radicals. The abilityof a mimetic to protect mammalian cells from xanthine/xanthineoxidase-induced injury can be assessed, for example, by growing rat L2cells in 24-well dishes. Cells can be pre-incubated with variousconcentrations of a mimetic and then xanthine oxidase (XO) can be addedto the culture along with xanthine (X). The appropriate amount of XO/Xused in the study can be pre-determined for each cell line by performinga dose-response curve for injury. X/XO can be used in an amount thatproduces approximately an LC₇₅ in the culture. Efficacy of the mimeticcan be correlated with a decrease in XO/X-induced LDH release.

[0047] The mimetics of the invention (particularly, metal bound formsthereof) can also be used as catalytic scavengers of reactive oxygenspecies to protect against ischemia reperfusion injuries associated withmyocardial infarction, coronary bypass surgery, stroke, acute headtrauma, organ reperfusion following transplantation, bowel ischemia,hemorrhagic shock, pulmonary infarction, surgical occlusion of bloodflow, and soft tissue injury. The mimetics (particularly, metal boundforms) can further be used to protect against skeletal musclereperfusion injuries. The mimetics (particularly, metal bound forms) canalso be used to protect against damage to the eye due to sunlight (andto the skin) as well as glaucoma, cataract and macular degeneration ofthe eye. The mimetics (particularly, metal bound forms) can also be usedto treat burns and skin diseases, such as dermatitis, psoriasis andother inflammatory skin diseases. Diseases of the bone are also amenableto treatment with the mimetics. Further, connective tissue disordersassociated with defects in collagen synthesis or degradation can beexpected to be susceptible to treatment with the present mimetics(particularly, metal bound forms), as should the generalized deficits ofaging. Liver cirrhosis and renal diseases (including glomerulanephritis, acute tabular necrosis, nephroderosis and dialysis inducedcomplications) are also amenable to treatment with the present mimetics(particularly, metal bond forms thereof).

[0048] The mimetics of the invention (particularly, metal bound forms)can also be used as catalytic scavengers of reactive oxygen species toincrease the very limited storage viability of transplanted hearts,livers, lungs, kidneys, skin and other organs and tissues. The inventionalso provides methods of inhibiting damage due to autoxidation ofsubstances resulting in the formation of O₂ including food products,pharmaceuticals, stored blood, etc. To effect this end, the mimetics ofthe invention are added to food products, pharmaceuticals, stored bloodand the like, in an amount sufficient to inhibit or prevent oxidationdamage and thereby to inhibit or prevent the degradation associated withthe autoxidation reactions. (For other uses of the mimetics of theinvention, see U.S. Pat. No. 5,227,4

5. The amount of mimetic to be used in a particular treatment or to beassociated with a particular substance can be determined by one skilledin the art.

[0049] The mimetics (particularly, metal bound forms) of the inventioncan further be used to scavenge hydrogen peroxide and thus protectagainst formation of the highly reactive hydroxyl radical by interferingwith Fenton chemistry (Aruoma and Halliwell, Biochem. J. 241:273 (1987):Meilo Filho et al. Biochem. J. 218:273 (1984); Rush and Bielski, J.Phys. Chem. 89:5062 (1985)). The mimetics (particularly, metal boundforms) of the invention can also be used to scavenge peroxynitrite, asdemonstrated indirectly by inhibition of the oxidation ofdihydrorhodamine 123 to rhodamine 123 and directly by acceleratingperoxynitrite degradation by stop flow analysis.

[0050] Further examples of specific diseases disorders appropriate fortreatment using the mimetics of the present invention, advantageously,metal bound forms, include diseases of the cardiovascular system(including cardiomyopathy, ischemia and atherosclerotic coronaryvascular disease), central nervous system (including AIDS dementia,stroke, amyotrophic lateral sclerosis (ALS), Parkinson's disease andHuntington's disease) and diseases of the musculature (includingdiaphramic diseases (eg respiratory fatigue in chronic obstructivepulmonary disease, cardiac fatigue of congestive heart failure, muscleweakness syndromes associated with myopathies, ALS and multiplesclerosis). Many neurologic disorders (including epilepsy, stroke,Huntington's disease, Parkinson's disease, ALS, Alzheimer's and AIDSdementia) are associated with an over stimulation of the major subtypeof glutamate receptor, the NMDA (or N-methyl-D-aspartate) subtype. Onstimulation of the NMDA receptor, excessive neuronal calciumconcentrations contribute to a series of membrane and cytoplasmic eventsleading to production of oxygen free radicals and nitric oxide (NO•).Interactions between oxygen free radicals and NO• have been shown tocontribute to neuronal cell death. Well-established neuronal corticalculture models of NMDA-toxicity have been developed and used as thebasis for drug development. In these same systems, the mimetics of thepresent invention inhibit NMDA induced injury. The formation of O₂ ⁻radicals is an obligate step in the intracellular events culminating inexcitotoxic death of cortical neurons and further demonstrate that themimetics of the invention can be used to scavenge O₂ ⁻ radicals andthereby serve as protectants against excitotoxic injury.

[0051] The present invention also relates to methods of treating AIDS.The Nf Kappa B promoter is used by the HIV virus for replication. Thispromoter is redox sensitive, therefore, an oxidant can regulate thisprocess. This has been shown previously for two metalloporphyrinsdistinct from those of the present invention (Song et al. AntiviralChem. and Chemother. 8:85 (1997)). The invention also relates to methodsof treating systemic hypertension, atherosclerosis, edema, septic shock,pulmonary hypertension, including primary pulmonary hypertension,impotence, infertility, endometriosis, premature uterine contractions,microbial infections, gout and in the treatment of Type I or Type IIdiabetes mellitus. The mimetics of the invention (particularly, metalbound forms) can be used to ameliorate the toxic effects associated withendotoxin, for example, by preserving vascular tone and preventingmulti-organ system damage.

[0052] As indicated above, inflammations, particularly inflammations ofthe lung, are amenable to treatment using the present mimetics(particularly, metal bound forms) (particularly the inflammatory baseddisorders of emphysema, asthma, ARDS including oxygen toxicity,pneumonia (especially AIDS-related pneumonia), cystic fibrosis, chronicsinusitis, arthritis and autoimmune diseases (such as lupus orrheumatoid arthritis)). Pulmonary fibrosis and inflammatory reactions ofmuscles, tendons and ligaments can be treated using the present mimetics(particularly metal bound forms thereof). EC-SOD is localized in theinterstitial spaces surrounding airways and vasculature smooth musclecells. EC-SOD and O₂ ⁻ mediate the antiinflammatory-proinflammatorybalance in the alveolar septum. NO• released by alveolar septal cellsacts to suppress inflammation unless it reacts with O₂ ⁻ to form ONOO⁻.By scavenging O₂ ⁻, EC-SOD tips the balance in the alveolar septumagainst inflammation. Significant amounts of ONOO⁻ will form only whenEC-SOD is deficient or when there is greatly increased O₂ ⁻ release.Mimetics described herein can be used to protect against destructioncaused by hyperoxia.

[0053] The invention further relates to methods of treating memorydisorders. It is believed that nitric oxide is a neurotransmitterinvolved in long-term memory potentiation. Using an EC-SOD knocked-outmouse model (Carlsson et al. Proc. Natl. Acad. Sci. USA 92:6264 (1995)).It can be shown that learning impairment correlates with reducedsuperoxide scavenging in extracellular spaces of the brain. Reducedscavenging results in higher extracellular O₂ ⁻ levels. O₂ ⁻ is believedto react with nitric oxide thereby preventing or inhibiting nitricoxide-mediated neurotransmission and thus long-term memory potentiation.The mimetics of the invention, particularly, metal bound forms, can beused to treat dementias and memory/learning disorders.

[0054] The availability of the mimetics of the invention also makespossible studies of processes mediated by O₂ ⁻, hydrogen peroxide,nitric oxide and peroxynitrite.

[0055] The mimetics described above, metal bound and metal free forms,can be formulated into pharmaceutical compositions suitable for use inthe present methods. Such compositions include the active agent(mimetic) together with a pharmaceutically acceptable carrier, excipientor diluent. The composition can be present in dosage unit form forexample, tablets, capsules or suppositories. The composition can also bein the form of a sterile solution suitable for injection ornebulization. Compositions can also be in a form suitable for opthalmicuse. The invention also includes compositions formulated for topicaladministration, such compositions taking the form, for example, of alotion, cream, gel or ointment. The concentration of active agent to beincluded in the composition can be selected based on the nature of theagent, the dosage regimen and the result sought.

[0056] The dosage of the composition of the invention to be administeredcan be determined without undue experimentation and will be dependentupon various factors including the nature of the active agent (includingwhether metal bound or metal free), the route of administration, thepatient, and the result sought to be achieved. A suitable dosage ofmimetic to be administered IV or topically can be expected to be in therange of about 0.01 to 50 mg/kg/day, preferably, 0.1 to 10 mg/kg/day.For aerosol administration, it is expected that does will be in therange of 0.001 to 5.0 mg/kg/day, preferably, 0.01 to 1 mg kg/day.Suitable doses of mimetics will vary, for example, with the mimetic andwith the result sought.

[0057] Certain aspects of the present invention will be described ingreater detail in the non-limiting Examples that follow. (The numberingof the compounds in Example I is for purposes of that Example only.)

EXAMPLE I Syntheses

[0058] I.[5,15-Bis(4-carbomethoxyphenyl)-10,20-(thiazol-5-yl)porphyrinato]-manganese(III)Chloride (5).

[0059] 1. meso-(Thiazol-5-yl)dipyrromethane (2).

[0060] In a foil-covered 250-mL three-necked flask, equipped with amagnetic stirrer and N₂ inlet, was placed 5-thiazolecarboxaldehyde (1.0.88 g, 7.81 mmol) (Dondoni, A.; Fantin, G.; Fogagnolo, M., Medici, A.,Pedrini, P. Synthesis 1987, 998-1001), CH₂Cl₂ (30 mL), and pyrrole (6mL, 87 mmol). The reaction mixture was stirred for 10 min. then TFA(0.25 mL, 3.2 mmol) was added. After a stirring period of 2 h at roomtemperature, the reaction mixture was transferred to a separatory funneland washed with saturated aqueous NaHCO, (50 mL), H₂O (50 mL) and brine(50 mL). The organic layer was dried (Na₂SO₄), filtered, andconcentrated in vacuo. The residue was dissolved in CH₂Cl₂ (50 mL) andadsorbed onto silica gel (3 g). Purification by column chromatography(gradient elution 33-67% EtOAc hexanes) provided dipyrromethane 2 (0.95g, 52%) as a gray solid: ¹H NMR (300 MHz. CDCl₃) δ 5.74 (s, 1 H), 6.02(m, 2 H), 6.17 (m, 2 H), 6.70 (m, 2 H), 7.58 (s, 1 H), 8.19 (br s, 2 H),8.68 (s, 1 H).

[0061] 2. 5,15-Bis(4-carbomethoxyphenyl)-10,20-(thiazol-5-yl)porphyrin(4).

[0062] In a foil-covered 250-mL three-necked round bottom flask,equipped with a magnetic stirrer and a N₂ outlet, was added methyl4-formylbenzoate (3. 180 mg. 1.09 mmol), dipyrromethane 2 (249 mg, 1.09mmol), and CH₂Cl₂ (110 mL). The reaction mixture was stirred for 15 min.then TFA (0.25 mL, 3.25 mmol) was added. After a stirring period of 2.5h at room temperature, DDQ (372 mg, 1.64 mmol) was added. The reactionmixture was stirred overnight and the solvent was removed in vacuo. Thecrude residue was adsorbed onto silica gel (3 g) then purified by columnchromatography (gradient elution 0-1.5% MeOH/CH₂Cl₂) to provideporphyrin 4 (80 mg, 10% yield) as a purple solid: ¹H NMR (300 MHz,CDCl₃) δ −275 (s, 2 H), 4.11 (s, 6 H), 8.28 (d, 4 H), 8.47 (d, 4 H),8.65 (s, 2H), 8.82 (d, 4 H), 8.99 (d, 4 H), 9.33 (s, 2 H).

[0063] 3.[5,15-Bis(4-carbomethoxyphenyl)-10,20-(thiazol-5-yl)porphyrinato]-manganese(III)Chloride (5).

[0064] A solution of porphyrin 4 (75 mg, 0.101 mmol) and MnCl₂ (129 mg,1.03 mmol) in DMF (15 mL) was heated at 125° C. for 14.5 h. The mixturewas cooled to room temperature while exposed to a stream of air, thenconcentrated in vacuo. Repeated chromatographic purification of theproduct (gradient elution 5-10% MeOH/CH₂Cl₂) provided porphryin 5 (7 mg,8%) as a dark green solid: mp>300° C.; UV-vis λ_(max)=466.0 nm,ε=1.34×10⁵ L/cm-mol; API MS m/z=797 [C

2H₂₆MnN₆O₄S₂].

[0065] II. [5,10,15,20-Tetrakis(thiazol-5-yl)porphyrinato]manganese(III)Chloride (7) and[5,10,15,20-Tetrakis(methylthiazolium-5-yl)porphyrinato]-manganese(III)Pentachloride (9).

[0066] 1. 5,10,15,20-Tetrakis(thiazol-5-yl)porphyrin (6).

[0067] A 250-mL three-necked flask equipped with a condenser and chargedwith propionic acid (60 mL) was heated to reflux.5-Thiazolecarboxaldehyde (1,373 mg, 3.30 mmol), pyrrole (230 μL, 3.32mmol), and an additional 5 mL of propionic acid were added. After 3.5 hat reflux, the mixture was cooled to room temperature while exposed to astream of air. The solvent was removed in vacuo, the residue wasredissolved in CHCl₃/MeOH/concentrated NH₄OH (6:3:1; 100 mL), and thesolvent was removed in vacuo. The residue was adsorbed onto silica gel(3 g) and purified by column chromatography (gradient elution. 1-2%MeOH/CH₂Cl₂) to provide porphyrin 6 (123 mg, 14%) as a solid: ¹H NMR(300 MHz, CDCl₂) δ −2.70 (s, 2 H), 8.67 (s, 4 H), 9.02 (s, 8 H), 9.38(s, 4 H).

[0068] 2. [5,10,15,20-Tetrakis(thiazol-5-yl)porphyrinato]manganese(III)Chloride (7).

[0069] A solution of porphyrin 6 (61 mg, 0.115 mmol) and MnCl₂ (144 mg,1.14 mmol) in DMF (15 mL) was heated at 125° C. for 7.5 h. A stream ofair was introduced and the reaction mixture was warmed to 130° C. Aftera stirring period of 1.5 h, the reaction mixture was cooled to roomtemperature. The solvent was evaporated in vacuo, and the residue wasadsorbed onto silica gel (2 g). Purification by column chromatograhy(gradient elution, 10-20% MeOH/CH₂Cl₂) provided porphyrin 7 (36 mg, 43%) as a dark green solid: mp>300° C.; UV-vis λ_(max)=466.5 nm, ε=3.55×10⁴L/cm-mol; FAB MS m/z=695 [C₃₂H₁₆MnN₃S₁]⁻.

[0070] 3. 5,10,15,20-Tetrakis(3-methylthiazolium-5-yl)porphyrinTetrachloride (8).

[0071] A solution of 6 (123 mg, 0.19 mmol). CH₃I (5 mL), and DMF (5 mL)in a sealed tube was heated at 100° C. for 24 h. The crude porphyriniodide salt that precipitated out of the reaction mixture was filtered,washed alternately with CH₂ Cl₂ and ether, and dried under vacuum atroom temperature. The iodide was dissolved in water, precipitated out asthe hexafluorophosphate salt (by dropwise addition of aqueous NH₄ ⁻PF

⁻ solution; 1 g/10 mL), filtered, washed with water and isopropanol, andvacuum dried at room temperature. The hexafluorophosphate salt wasdissolved in acetone then filtered (to remove insoluble solids). Theproduct was precipitated out as the chloride salt from the filtrate bydropwise addition of a solution of Bu₄NH₄ ⁻Cl⁻ in acetone (1 g/10 mL),filtered, washed with copious quantities of acetone, and dried undervacuum at room temperature, to provide porphyrin 8 (66 mg, 41%): ¹H NMR(300 MHz DMSO-d₅) −3.1 (s, 2 H), 4.6 (s, 12 H), 9.49 (s, 4 H), 9.58 (s,8 H), 10.85 (s, 4 H).

[0072] 4.[5,10,15,20-Tetrakis(3-methylthiazolium-5yl)porphyrinato]manganese(III)Pentachloride (9).

[0073] Porphyrin 8 (60 mg. mmol) was dissolved in water (15 mL) and thesolution pH was adjusted to pH=12 by dropwise addition of 6N NaOH. SolidMnCl₂ (147 mg) was added into the reaction mixture (the resultingpH=8.7). After a stirring period of 30-60 min. the reaction mixture wasfiltered through a fritted funnel lined with a filter paper. The pH ofthe filtrate was adjusted to pH=4.5 (1N HCl) then the solution wasfiltered. Purification by the double precipitation method (as describedfor the preparation of 8) provided porphyrin 9

[0074] (6 mg, 8.2%) as a dark brown solid: mp>300° C.; UV-visλ_(max)=460.00 nm. ε=1.25×10⁵ L/cm-mol.

[0075] III. [5,15-Bis(thiazol-5-yl)porphyrinato]manganese(III) Chloride(12).

[0076] 1. 5,15-Bis(thiazol-5yl)porphyrin (11).

[0077] In a foil-covered 500-mL three-necked round bottom flask,equipped with magnetic stirrer and a N₂ inlet, was added dipyrromethane10 (288 mg, 1.97 mmol) (Chong, R.; Clezy, P. S.; Liepa, A. J.; Nichol,A. W. Austin J. Chem. 1969, 22, 229), 5-thiazolecarboxaldehyde (1,223mg, 1.97 mmol), CH₂Cl₂ (198 mL) and sodium chloride (13 mg, 0.2 mmol).The reaction mixture was stirred vigorously for 10 min, then TFA (0.46mL, 5.97 mmol) was added. After a stirring period of 40 min, DDQ (671mg, 2.96 mmol) was added, and the reaction mixture was stirred for anadditional 4 h. The solvent was evaporated in vacuo, and the residue wasadsorbed onto silica gel (3 g). Repeated chromatogaphic purification(gradient elution 0.5-2% MeOH/CH₂Cl₂) provided porphyrin 11 (23 mg, 6%)as a solid: ¹H NMR (300 MHz, CDCl₃) δ −3.07 (s, 2 H), 8.69 (s, 2 H),9.21 (d, 4 H), 9.39 (s, 2 H), 9.43 (d, 4 H), 10.35 (s, 2 H).

[0078] 2. [5,15-Bis(thiazol-5-yl)porphyrinato]manganese(III) Chloride(12).

[0079] A solution of porphyrin 11 (28 mg, 0.0587 mmol) and MnCl₂ (85 mg,0.675 mmol) in DMF (8 mL) was heated at 125° C. for 15 h. The mixturewas cooled to room temperature while exposed to a stream of air, and thesolvent was removed by rotary evaporation. The residue was dissolved in10% MeOH/CH₂Cl₂ (50 mL) and adsorbed onto silica gel (500 mg).Purification by column chromatography (gradient of 5-10% MeOH/CH₂Cl₂)provided porphyrin 12 (29 mg, 86%) as a dark brown solid: mp>300° C.;UV-vis λ_(max)=457.5 nm. ε=3.75×10⁴ L/cm-mol; API MS m/z=529[C₂₆H₁₄MnN₆S₂]⁻.

[0080] IV.[5,15Bis(4-carbomethoxyphenyl)-10,20-bis(3-methylthiazolium-2-yl)porphyrinato]manganese(III)Trichloride (16).

[0081] 1. meso-(Thiazol-2-yl)dipyrromethane (14).

[0082] In a foil-covered 250-mL three-necked flask, equipped with amagnetic stirrer and a N₂ inlet, was placed 2-thiazolecarboxaldehyde(13, 0.97 g, 8.6 mmol) (Dondoni, A.; Fantin, G.; Fogagnolo, M.; Medici,A.; Pedrini, P. Synthesis 1987, 998-1001), CH₂Cl₂ (35 mL), and pyrrole(7.2 mL, 104 mmol). The reaction mixture was stirred for 10 min, thenTFA (0.26 mL, 3.4 mmol) was added. After a stirring period of 1 h atroom temperature, the reaction mixture was transferred to a separatoryfunnel and washed with saturated aqueous NaHCO₃ (50 mL), H₂O (50 mL),and brine (50 mL). The organic layer was dried (Na₂SO₄), filtered andconcentrated in vacuo. The residue was dissolved in CH₂Cl₂ (50 mL), andadsorbed onto silica gel (3 g). Purification by column chromatography(1:1 ether hexanes) provided dipyrromethane 14 (1.22 g, 62%) as a solid:¹H NMR (300 MHz, CDCl₃) δ 5.78 (s, 1 H), 6.04 (s, 2 H), 6.15 (m, 2 H),6.71 (m, 2 H), 7.20 (d, 1 H), 7.74 (d, 1 H), 8.81 (br s, 1 H).

[0083] 2. 5,15-Bis(4-carbomethoxyphenyl)-10,20-(thiazol-2-yl)porphyrin(15).

[0084] In a foil-covered 500-mL three-necked round bottom flask,equipped with a magnetic stirrer and a N₂ outlet, was addeddipyrromethane 14 (771 mg, 3.39 mmol). methyl 4-formylbenzoate (3. 0.557g, 3.36 mmol) and CH₂Cl₂ (350 mL). The reaction mixture was stirred for15 min, then TFA (0.8 mL, 10.4 mmol) was added. After a stirring periodof 3 h at room temperature, DDQ (1.16 g. 1.64 mmol) was added. Thereaction mixture was stirred for 3 d, then the solvent was removed invacuo. The residue was adsorbed onto silica gel (4 g) and purified bycolumn chromatography (gradient elution 0.5-1% MeOH/CH₂Cl₂) to provideporphyrin 15 (140 mg, 11%) as a purple solid: (300 MHz, CDCl₅) δ −2.29(s, 2 H), 4.12 (s, 6 H), 8.02 (d, 2 H), 8.30 (d, 4 H), 8.44 (d, 2 H),8.47 (d, 4 H), 8.84 (d, 4 H), 9.05 (d, 4 H).

[0085] 3.[5,15-Bis(4carbomethoxyphenyl)-10,20-bis(3-methylthiazolium-2-yl)-porphyrinato]manganese(III)Trichloride (16).

[0086] A solution of porphyrin 15 (26 mg, 0.054 mmol) and MnCl₂ (40 mg,0.40 mmol) in DMF (20 mL) was heated at 135° C. overnight. The mixturewas cooled to 45° C. and CH₃I (0.8 mL, 11.2 mmol) was added. Thereaction mixture was stirred for 36 h at 45° C. and DMF was evaporatedin vacuo. The residue was purified by column chromatography (gradientelution EtOAc. CHCl₃, MeOH, concentrated NH₄OH) to provide the productcontaminated with impurities. Following a second purification by columnchromatography (6:3:1 CHCl₃, MeOH concentrated NH₂OH) non-polarfractions were collected leaving the bulk of product at the top of thecolumn. The top silica gel containing the product was collected andwashed with CHCl₃/MeOH/1N HCl (6:4:1). Evaporation of the acidicsolution provided the product that contained excess inorganic salts.Purification by the double precipitation method and vacuum drying at 35°C. for 2 d provided porphyrin 16 (9 mg, 28%) as a black solid: mp>300°C.; UV-vis λ_(max)=459.0 nm: ε=1.36×10⁵ L/cm-mol: API MS m/z=886 [C

H₃₂MnN

O

S

—CH₃CO₂]⁻².

[0087] V. [5,15-Bis(3-methylthiazolium-2-yl)porphyrinato]manganese(III)Trichloride (19).

[0088] 1. 5,15-Bis(thiazol-2-yl)porphyrin (17).

[0089] In a foil-covered 500-mL three-necked round bottom flask,equipped with magnetic stirrer and a N₂ inlet, was added dipyrromethane(10, 677 mg, 4.6 mmol), 2-thiazol-carboxaldehyde (13, 524 mg, 4.6 mmol),and CH₁Cl₂ (450 mL). The reaction mixture was stirred for 10 min, thenTFA (1 mL, 16.9 mmol) was added. After a stirring period of 1 h, DDQ(1.58 g, 7 mmol) added and the reaction mixture was stirred overnight.The solvent was evaporated in vacuo, and the residue was adsorbed ontosilica gel (3 g). Repeated purification by column chromatography(gradient elution 1-2% MeOH/CH₂Cl₂) provided porphyrin 17 (51 mg, 4.62%) as a purple solid: ¹H NMR (300 MHz CDCl

)

-3.05 (s, 2 H), 8.06 (d, 2 H), 8.51 (d, 2 H), 9.35 (d, 4 H), 9.45 (d,4H), 10.40 (s, 2 H).

[0090] 2. 5,15-Bis(3-methylthiazolium-2-yl)porphyrin Dichloride (18).

[0091] A solution of porphyrin 17 (140 mg, 0.29 mmol), CH₃I (4 mL), andDMF (20 mL) in a sealed tube was heated at 100° C. for 48 h. Theprecipitate that formed during the reaction was filtered and washed withether. Purification of the solid precipitate by the double precipitationmethod provided porphyrin 18 (120 mg. 71%) as a purple solid: ¹H NMR(300 MHz. DMSO-d

) δ −3.4 (s, 2 H), 4.09, 4.06 (2 s, 6 H, atropisomer N

CH₃), 9.07 (d, 2 H), 9.2 (d, 2 H), 9.4 (d 4 H), 9.9 (d, 4 H) 10.96 (s, 2H).

[0092] 3. [5,15-Bis(3-methylthiazolium-2-yl)porphyrinato]manganese(III)Trichloride (19).

[0093] Porphyrin 18 (120 mg, 0.21 mmol) was dissolved in water (25 mL)and the solution pH was adjusted to pH=12 by dropwise addition of 6NNaOH. Solid MnCl₂ (147 mg) was added (the resulting pH 8.7) and thereaction mixture was stirred for 30-60 min. The reaction mixture wasfiltered through a fritted funnel lined with a filter paper. The pH ofthe filtrate was adjusted to pH=4-5 (1N HCl) and the solution wasfiltered. The filtrate was subjected to the double precipitation methodto provide a mixture of porphyrins 18 and 19. The resulting mixture wasseparated by column chromatography (9:0.5:0.5 CH₃CN/water/saturatedKNO₃) to provide porphyrin 19 (25 mg, 18%) as a dark solid: mp>300° C.;UV-vis λ_(max)=450.5 nm, ε=5.99×10⁴ L/cm-mol.

[0094] VI.[5,10,15,20-Tetrakis(1-methylimidazol-2-yl)porphyrinato]manganese(III)Chloride (22) and[5,10,15,20-Tetrakis(1,3-dimethylimidazolium-2-yl)-porphyrinato]manganese(III)Pentachloride (24)

[0095] 1. 5,10,15,20-Tetrakis(1-methylimidazol-2-yl)porphyrin (21).

[0096] In a foil-covered 1-L three-neck flask quipped with magneticstirrer, thermometer, and condenser was placed aldehyde 20 (2.0 g, 18.2mmol) and propionic acid (400 mL). The reaction mixture was heated to120° C. at which time pyrrole (1.26 mL, 18.2 mmol) was added. Thereaction mixture was heated under reflux for an additional 4.5 h and wasstirred at room temperature for 3 d. The propionic acid was removed invacuo, the dark, residue was dissolved in a solution of 5% MeOH/CH₂Cl₂and adsorbed onto silica gel (18 g). Repeated column chromatographicpurification provided porphyrin 21 (280 mg, 10%) as a purple solid: ¹HNMR (300 MHz, CDCl₃) δ −2.94, −2.90, −2.84 (3 s, 2 H. atropisomer NH

. 3.39-3.58 (multiple s. 12 H. atropisomer N—CH

), 7.50 (d. 4 H), 7.71 (d. 4 H), 8.92 (m. 8 H).

[0097] 2.[5,10,15,20-Tetrakis(1-methylimidazol-2-yl)porphyrinato]manganese(III)Chloride (22).

[0098] A solution of porphyrin 21 (29.9 mg, 0.047 mmol) and MnCl₂ (61mg, 0.48 mmol) in DMF (12 mL) was heated at 120° C. for 14 h. Themixture was cooled to room temperature while exposed to a stream of air,and concentrated by rotary evaporation. Purification by columnchromatography (CHCl₃/MeOH/concentrated NH₄OH/EtOAc) provided porphyrin22 (12.5 mg, 37%) as a black solid: mp>300° C. UV-vis λ_(max)=463.0 nm:ε=9.35×10⁴ L/cm-mol; API MS m/z=683 [C₃₆H₂₈MnN₁₂]⁻.

[0099] 3. 5,10,15,20-Tetrakis(1,3-dimethylimidazolium-2-yl)porphyrinTetrachloride (23).

[0100] A solution of porphyrin 21 (589 mg, 0.934 mmol) and CH₃I (3 mL,48 mmol) in DMF (10 mL) was heated in a sealed tube at 100° C. for 14 h.The reaction mixture was poured into ethyl acetate (200 mL) causingporphyrin 23 to precipitate as the iodide salt. The solution wasfiltered and the brown solid was washed with EtOAc and ether. Theproduct was purified by column chromatography (CH₃CN/water/saturatedKNO₃) and subjected to the double precipitation method to provideporphyrin 23 (540 mg, 69%) as a purple solid: ¹H NMR (300 MHz, DMSO-d₅)δ −3.22 (s, 2 H), 3.78 (s, 24 H), 8.60 (s, 8 H), 9.44 (s, 8 H).

[0101] 4.[5,10,15,20-Tetrakis(1,3-dimethylimidazolium-2-yl)porphyrinato]manganese(III)Pentachloride (24).

[0102] Porphyrin 23 (1.0 g, 0.33 mmol) was dissolved MeOH (550 mL) thenMnCl₂ (1.57 g, 12.5 mmol) was added. The solution pH was adjusted topH=7.3 with 6N NaOH while bubbling a stream of air into the reactionmixture. The pH of the solution was maintained pH>7.3 for 1 h thenadjusted to pH=4.5 with 1N HCl. The solution was filtered and theprecipitate subjected to the double precipitation method and dried toprovide porphyrin 24 (0.570 g, 74%) as a solid: mp>300° C.; UV-visλ_(max)=460.5 nm; ε=8.38×10⁴ L/cm-mol: FAB MS m/z=778 [C

0H

0MnN₁₂]⁻⁴.

[0103] VII.[5,15-Bis(4-carbomethoxyphenyl)-10,20-bis(1-methylimidazol-2-yl)-porphyrinato]manganese(III)Chloride (27) and[5,15-Bis(4-carbomethoxyphenyl)-10,20-bis(1,3-dimethylimidazolium-2-yl)porphyrinato]manganese(III)Trichloride (29).

[0104] 1.5,15-Bis(4-carbomethoxyphenyl)-10,20-bis(1-methylimidazol-2-yl)porphyrin(26).

[0105] In a foil-covered 500-mL three-necked flask, equipped with amagnetic stirrer and N₂ inlet was placed dipyrromethane 25 (0.71 g, 3.09mmol), CH₂Cl₂ (310 mL), aldehyde 4 (50 mg, 3.09 mmol), and NaCl (22.4mg, 0.35 mmol). The reaction mixture was stirred for 10 min, then TFA(1.48 mL, 19.2 mmol) was added. After a stirring period of 4 h at roomtemperature, DDQ (1.05 g, 4.65 mmol) was added. The reaction mixture wasstirred overnight and the solvent was removed in vacuo. The residue wasadsorbed onto silica gel (10 g) then purified by column chromatography(gradient elution 2-4% EtOAc/hexanes) to provide porphyrin 26 (220 g. 24%) as a purple solid: ¹H NMR (300 MHz. CDCl₃) δ −2.85 (s, 2 H), 3.43,3.49 (2s, 6 H, atropisomer N—CH₃), 4.14 (s, 6 H), 7.49 (d, 2 H), 7.68(d, 2 H), 8.30 (d, 4 H), 8.48 (d, 4 H) 8.87 (m, 8 H).

[0106] 2.[5,15-Bis(4-carbomethoxyphenyl)-10,20-bis(1-methylimidazol-2-yl)-porphyrinato]manganese(III)Chloride (27).

[0107] A solution of porphyrin 26 (50.7 mg. 0.071 mmol) and MnCl₂ (88.6mg, 0.70 mmol) in DMF (20 mL) was heated at 120° C. for 14 h. Themixture was cooled to room temperature while exposed to a stream of air,then concentrated by rotary evaporation. Purification by columnchromatography (gradient elution 5-10% MeOH/CH₂Cl

) provided porphyrin 27 (25 mg, 42%) as a black solid: mp>300° C.;UV-vis λ_(max)=463.0 nm; ε=6.70×10

L/cm-mol; FAB MS m/z=791 [C₄₄H₃₂MnN₃O₄]⁻.

[0108] 3.3,15-Bis(4-carbomethoxyphenyl)-10,20-bis(1,3-dimethylimidazolium-2-yl)-porphyrinDichloride (28).

[0109] A solution of porphyrin 26 (80 mg, 0.11 mmol), DMF (7 mL) andCH₃I (0.150 mL) was stirred at room temperature for 4 h. The solvent wasremoved by rotary evaporation to give a dark colored residue. Theresidue was purified by column chromatography (CHCl₃/MeOH/concentratedNH₄OH/EtOAc) to provide porphyrin 28 (21 mg. 18%) as a purple solid: ¹HNMR (300 MHz. DMSO-d₅) δ −3.02 (s, 2 H), 3.73 (s, 12 H), 4.08 (s, 6 H),8.45 (q, 8 H), 8.56 (s, 4 H), 9.13 (s, 8 H): API MS m/z=384[C₁₆H₄₀MnN₃O₄]⁻².

[0110] 4.[5,15-Bis(4-carbomethoxyphenyl)-10,20-bis(1,3-dimethylimidazolium-2-yl)-porphyrinato]manganese(III)Trichloride (29).

[0111] A solution of porphyrin 28 (19.5 mg, 0.022 mmol) and MnCl₂ (22.4mg, 0.18 mmol) in DMF (5 mL) was heated at 120° C. for 14 h. Thereaction mixture was cooled to room temperature while exposed to astream of air, then concentrated by rotary evaporation. Purification bycolumn chromatography (CHCl₃/MeOH/concentrated NH

OH/EtOAc) provided crude porphyrin 28. Purification by the doubleprecipitation method and drying provided porphyrin 29 (6.5 mg, 37%) as asolid: mp>300° C.; UV-vis λ_(max)=447.5 nm; ε=1.27×10⁵ L/cm-mol; FAB MSm/z=856 [C₄₆H₃₈MnN₃O

]⁻².

[0112] VIII.[5,15-Bis(carboethoxy)-10,20-bis(1-methylimidazol-2-yl)porphyrinato]-manganese(III)Chloride (32).

[0113] 1. 5,15-Bis(carboethoxy -10,20-bis(1-methylimidazol-2yl)porphyrin(31).

[0114] In a foil-covered 500-mL three-necked flask, equipped with amagnetic stirrer and N₂ inlet, was placed dipyrromethane 25 (0.5 g, 2.2mmol), CH₂Cl₂ (220 mL), and aldehyde 30 (225 mg, 2.2 mmol). The reactionmixture was stirred for 10 min, then TFA (1.0 mL, 12.9 mmol) was added.After a stirring period of 2 h at room temperature, DDQ (750 mg, 3.3mmol) was added, and the reaction mixture was stirred overnight.Triethylamine (2.0 mL) was added, the solvent was evaporated in vacuo,and the residue adsorbed onto silica gel (10 g). Purification by columnchromatography (5% EtOH/CHCl

) provided porphyrin 31 (86 mg, 13%) as a purple solid: ¹H NMR (300 MHz,CDCl₃) δ −3.08, −3.06 (2 s, 2 H, atropisomer NH), 1.82 (t, 6 H), 3.40,3.49 (2 s, 6 H, atropisomer N—CH₃), 5.11 (q, 4 H), 7.53 (d, 2 H), 7.72(d, 2 H), 8.94 (m, 4 H), 9.50 (d, 4 H).

[0115] 2.[5,15-Bis(carboethoxy)-10,20-bis(1-methylimidazol-2-yl)porphyrinato]-manganese(III)Chloride (32).

[0116] A solution of porphyrin 31 (27.7 mg, 0.045 mmol) and MnCl₂ (59.1mg, 0.47 mmol) in DMF (112.5 mL) was heated at 120° C. for 14 h.Additional MnCl₂ (29 mg, 0.23 mmol) was added and the reaction mixturewas heated for another 2 h. The reaction mixture was cooled to roomtemperature while exposed to a stream of air, then concentrated byrotary evaporation. Air was bubbled into a solution of the productdissolved in ethanol with two drops of 1N HCl. The solvent wasevaporated in vacuo to give a dark colored residue. Purification bycolumn chromatography (gradient elution 10-30% EtOH/CHCl₃) providedporphyrin 32 (6.5 mg. 35%) as a black solid: mp>300° C.: UV-visλ_(max)=458.5 nm; ε=6.01×10

L/cm-mol. API MS m/z=667 [C₃₄H

2

MnN₃O

]⁻¹.

[0117] IX. [5,15-Bis(1-methylimidazol-2-yl)porphyrinato]manganese(III)Chloride (34) and[5,15-Bis(1,3-dimethylimidazolium-2-yl)porphyrinato]manganese(III)Trichloride (36).

[0118] 1. 5,15-Bis(1-methylimidazol-2-yl)porphyrin (33).

[0119] In a foil-covered 1-L three-necked flask equipped with a magneticstirrer and N₂ inlet, was placed dipyrromethane 10 (1.0 g, 6.84 mmol),CH₂Cl₂ (680 mL), and aldehyde 20 (753 mg, 6.84 mmol). The reactionmixture was stirred for 10 min, then TEA (3.1 mL, 40.2 mmol) was added.After a stirring period of 2 h at room temperature, DDQ (2.3 g, 10.1mmol) was added and the reaction mixture was stirred overnight.Triethylamine (5.75 mL) was added into the reaction mixture, the solventwas evaporated in vacuo and the residue was adsorbed onto silica gel (15g). Purification by column chromatography (6% MeOH/CH₂Cl₂) providedporphyrin 33 (0.120 g, 7%) as a purple solid: ¹H NMR (300 MHz, CDCl₃) δ−3.28 (s, 2 H), 3.45, 3.52 (2 s, 6 H, atropisomer N—CH₃), 7.53 (d, 2 H),7.74 (d, 2 H), 9.07 (m, 4 H), 9.46 (d, 4 H), 10.37 (s, 2 H).

[0120] 2. [5,15-Bis(1-methylimidazol-2-yl)porphyrinato]manganese(III)Chloride (34).

[0121] A solution of porphyrin 33 (50 mg, 0.106 mmol) and MnCl₂ (180 m.,1.4 mmol) in DMF (20 mL) was heated at 120° C. for 14 h. The mixture wascooled to room temperature while exposed to a stream of air, thenconcentrated by rotary evaporation. Purification by columnchromatography (33% MeOH/CHCl₃) provided porphyrin 34 (32 mg, 53%) as ablack solid: mp>300° C.; UV-vis λ_(max)=454.5 nm; ε=4.98×10⁴ L/cm-mol;API MS m/z=523 [C₂₈H₂₀MnN₃]⁻.

[0122] 3. 5,15-Bis(1,3-dimethylimidazolium-2-yl)porphyrin Dichloride(35).

[0123] Porphyrin 33 (95 mg, 0.20 mmol) was dissolved in DMF (15 mL).CH₃I (0.5 mL, 8.03 mmol) was added, and the reaction mixture stirred for48 h. The DMF was evaporated in vacuo and the dark colored residue waspurified by column chromatography (gradient elution 30% MeOH/CH₂Cl₂ to6:4:1 CHCl₃/MeOH/1N HCl) to provide porphyrin 35 (150 mg, 99%) as apurple solid: ¹H NMR (300 MHz. DMSO-d₆) δ −3.54; (s, 2 H), 3.79 (s, 12H), 8.55 (s 4 H), 9.28 (d, 4 H), 11.00 (s, 2 H).

[0124] 4.[5,15-Bis(1,3-dimethylimidazolium-2-yl)porphyrinato]manganese(III)Trichloride (36).

[0125] Porphyrin 35 (150 mg, 0.198 mmol) was dissolved in water (50 mL)and the solution pH was adjusted to pH=12 with 6NaOH. Manganese chloride(375 mg, 2.98 mmol) was added and the reaction mixture was stirred for30 min. The solution was filtered on a fine fritted filter funnel, thepH of the filtrate was adjusted to pH=4 (1N HCl) and the solution wasfiltered. Purification of the solid filter cake by the doubleprecipitation method and drying provided porphyrin 36 (25.5 mg, 20%) asa solid: mp>300° C.; UV-vis λ _(max)=447.5 nm; ε=8.66×10⁴ L/cm-mol; APIMS m/z=554 [C₃₀H₂₆MnN₃—H]

−

.

[0126] X.[5,10,15,20-Tetrakis(1,4,5-trimethylimidazol-2-yl)porphyrinato]-manganese(III)Chloride(39) and[5,10,15,20-Tetrakis(1,3,4,5-tetramethylimidazolium-2-yl)porphyrinato]manganese(III)Pentachloride(41).

[0127] 1. [5,10,15,20-Tetrakis(1,4,5-trimethylimidazol-2-yl)porphyrin(38).

[0128] 1,4,5-Trimethylimidazole-2-carboxaldehyde (37, 750 mg, 5.42mmol), prepared according to literature procedure (Alcalde, E. et al,Tetrahedron 52:15171-15188 (1996)), was dissolved in propionic acid (120mL) in a 250 mL three neck round-bottom flask equipped with athermometer and a condenser. The solution was heated to reflux thenpyrrole (0.38 mL, 5.42 mmol) was added. The reaction mixture was heatedat reflux for an additional 5 h. then cooled to room temperature whileexposed to air overnight. The propionic acid was removed by vacuumdistillation yielding a dark solid residue which was adsorbed ontosilica gel. Purification by column chromatography (gradient elution5-10% MeOH/CH₂Cl₂) provided porphyrin 38 as a mixture of atropisomers(108 mg. 10.7%). ¹H NMR (300 MHz, CDCl₃)δ−2.90, −2.90. −2.85, −2.78 s,2H. atropisomer NH). 2.50 (s, 12 H), 2.57 (s, 12 H), 3.15-3.42 (multiples. 12 H, atropisomer N—CH₃). 8.91 (multiple s, 8 H, atropisomer).

[0129] 2.[5,10,15,20-Tetrakis(1,4,5-trimethylimidazol-2-yl)porphyrinato]manganese(III)Chloride (39).

[0130] Porphyrin 38 (40 mg, 0.05 mmol) was dissolved in MeOH (7 mL) in a25 mL round-bottom flask equipped with a condenser. Manganese(II)chloride (101 mg. 0.81 mmol) was added and the reaction mixture washeated under reflux for 2 h. Air was bubbled into the reaction mixturefor 20 min then methanol was evaporated in vacuo. Purification of theresidue by column chromatography provided porphyrin 39 as a black solid(12 mg, 27%): mp>300° C.; UV-vis λ_(max)=474.5 nm. ε=9.74×10⁴L/cm-mol;API MS m/z=795[C₄₄H₄₄MnN₁₂]⁻.

[0131] 3.[3,10,15,20-Tetrakis(1,3,4,5-tetramethylimidazolium-2-yl)porphyrinTetraiodide (40).

[0132] Porphyrin 38 (40 mg, 0.05 mmol) was dissolved in DMF (5 mL) in asealed tube reactor. Methyl iodide (1 mL, 16 mmol) was added and thesealed tube heated at 60° C. overnight. Dilution of the reaction mixturewith EtOAc (100 mL) resulted in the precipitation of crude product 40which was collected by vacuum filtration then purified by columnchromatography to provide porphyrin 40 as a dark purple solid (25 mg,35%): ¹H NMR (300 MHz. DMSO-d₆)δ−3.20 (s, 2 H), 2.72 (s, 24 H), 3.58 (s,24 h), 9.40 (s, 8 H).

[0133] 4.[5,10,15,20-Tetrakis(1,3,4,5-tetramethylimidazolium-2-yl)porphyrinato]-manganese(III)Pentachloride (41).

[0134] Porphyrin 40 (25 mg, 0.02 mmol) was dissolved in methanol (7 mL)in a round-bottomed flask (25 mL). Manganese(II) chloride (50 mg, 0.4mmol) was added and the reaction mixture was heated at 60° C. for 6 h.NaOH (2N, 2 drops) was added and the reaction mixture stirred for anadditional hour. The reaction mixture was filtered through celite andwashed through with MeOH. Analysis of the filtrate by UV-visspectroscopy indicated that the reaction was incomplete. The solvent wasevaporated off and the residue redissolved in MeOH (7 mL), then MnCl₂(50mg, 0.4 mmol) was added and the reaction mixture was heated at 60° C.for 3 h. Air was bubbled into the reaction mixture for 20 min. Thereaction mixture was filtered over celite and washed with MeOH.Evaporation of the solvents in vacuo provided a brown residue.Purification of the product by the double precipitation method providedporphyrin 41 (10 mg, 51%) as a brown solid: mp>300° C.; UV-visλ_(max)=451 nm. ε=9.29×10⁴ L/cm-mol.

[0135] XI.[5,10,15,20-Tetrakis(4-methyl-1,2,4-triazol-3-yl)porphyrinato]manganese(III)Chloride (44).

[0136] 1. 5,10,15,20-Tetrakis(4-methyl-1,2,4triazol-3-yl)porphyrin (43).

[0137] 4-Methyl-1,2,4-trazole-2-carboxaldehyde (42, 1.06 g, 9.5 mmol),prepared according to literature procedure (Moderhack, D.; Hoppe-Tichy,T. J. Prakr. Chem/Chem-Ztg. 1996, 338(2), 169-171), was dissolved inpropionic acid (180 mL) in a 250-mL three-neck round bottom flaskcovered with foil and equipped with a condenser. The solution was heatedto reflux, and then pyrrole (0.66 mL, 9.5 mmol) was added. The reactionmixture was stirred at reflux for an additional 2.5 h. The reaction wasthen cooled to room temperature while exposed to air over 2 days.Evaporation of the propionic acid under reduced pressure provided a darkresidue which was adsorbed onto silica gel. Repeated purification bycolumn chromatography (gradient elution. CHCl₃, MeOH. concentratedNH₄OH. EtOAc) provided porphyrin 43 (219 mg, 14.6%) as a solid mixtureof atropiosomers: ¹H NMR (300 MHz DMSO-d

) δ −3.36, −3.13, −3.09 (3 s, 2H. atropisomer NH). 3.43-3.64 (multiples, 12 H, atropisomer N—CH₃), 9.03 (broad s, 8 H), 9.20 (s, 4 H.).

[0138] 2.[5,15,15,20-Tetrakis(4-methyl-1,2,4-triazol-3-yl)porphyrinato]manganese(III)Chloride (44).

[0139] Porphyrin 43 (77 mg, 0.12 mmol) was dissolved in DMF (30 mL) in a100-mL round bottom flask equipped with a condenser. Manganese (II)chloride (156 mg, 1.24 mmol) was added and the reaction was heated at130° C. overnight. The reaction mixture was exposed to a stream of airas it cooled to room temperature. The porphyrin precipitated out uponthe addition of CH₂Cl₂ (5-10 mL). The solids were filtered and washedwith EtOH and CH₂Cl₂ to provide porphyrin 44 (45 mg, 51%) as a brownsolid: mp>300° C.: UV-vis λ_(max)=452.5 nm: ε=8.10×10⁴ L/cm-mol; FAB-MSm/z=787 [C₃₂H₂₄MnN

1

]⁻.

[0140] XII.[5,15-Bis(trifluoromethyl)-10,20-bis(imidazol-2-yl)porphyrinato]-manganese(III)Chloride (47).

[0141] 1. 5,15-Bis(trifluoromethyl)-10,20-bis(imidazol-2-yl)porphyrin(46).

[0142] In a foil-covered 1-L three-neck round bottom flask, equippedwith a magnetic stirrer and a N₂ outlet, was added dipyrromethane 45(1.13 g, 5.28 mmol), 1-methylimidazole-2-carboxaldehyde (20, 582 mg,5.28 mmol), sodium chloride (32 mg, 0.54 mmol) and CH₂Cl₂ (530 mL). Thereaction mixture was stirred for 10 min, then TFA (2.40 mL, 31.1 mmol)was added. After a stirring period of 105 min, DDQ (1.81 g, 7.97 mmol)was added, and the mixture was stirred overnight. The solvent wasremoved by rotary evaporation, and the crude residue was adsorbed ontosilica gel (3 g). Purification by column chromatography (gradientelution, 5-10% MeOH/CH₂Cl₂) provided porphyrin 46 (455 mg, 34%) as ablack solid: ¹H NMR (300 MHz, CDCl₃) δ −2.87 (s, 2 H), 3.56 (m, 6 H),7.85 (d, 2 H), 8.05 (d, 2 H), 8.99 (m, 4 H), 9.81 (m, 4 H); API-MSm/z=607 [C₃₀H₂₀F₆N

—H]⁻¹.

[0143] 2.[5,15-Bis(trifluoromethyl)-10,20bis(imidazol-2-yl)porphyrinato]manganese(III)Chloride (47).

[0144] A solution of free porphyrin 46 (113 mg, 0.186 mmol) andMnCl₂(360 mg, 2.86 mmol) in DMF (15 mL) was warmed to 120° C. for 6 h.The mixture was cooled to room temperature while exposed to a stream ofair, then concentrated by rotary evaporation. The crude residue wasdissolved in 10% MeOH/CH₂Cl₂ (100 mL), then adsorbed onto silica gel (1g). Purification by column chromatography (10% MeOH/CH₂Cl₂) providedporphyrin 47 (45 mg, 35%) as a dark green solid: mp>300° C.; UV-visλ_(max)=456.5 nm; ε=1.98×10⁴ L/cm-mol; API-MS m/z=659 [C

0H₁₈F

MnN₃]⁻.

[0145] XIII.[5,10,15,20-Tetrakis(1-methylpyrazoyl-4-yl)porphyrinato]manganese(III)Chloride (50) and[5,10,15,20-Tetrakis(1,2-dimethylpyrazolium-4-yl)porphyrinato]-manganese)Pentachloride (52).

[0146] 1. 5,10,15,20-Tetrakis(1-methylpyrazol-4yl)porphyrin (49).

[0147] To a refluxing solution of propionic acid (200 mL) and1-methylpyrazole-4-carboxaldehyde (48, 0.92 g, 8.32 mmol), preparedaccording to literature procedure (Finar, I. L.; Lord, G. H. J. Chem.Soc. 1957, 3314 3315), was added pyrrole (0.63 mL, 8.32 mmol). Thereaction was covered with foil and was heated under reflux for 3.5 h.Upon cooling the reaction mixture was exposed to air overnight. Thepropionic acid was then removed by vacuum distillation. The cruderesidue was dissolved in 5% MeOH/CH₂Cl₂, then adsorbed onto silica gel(5.3 g). Purification by column chromatography (5% MeOH/CH₂Cl₂) providedporphyrin 49 as a purple solid (231 mg, 17.5%): ¹H NMR (300 MHz,DMSO-d₅) δ 2.74 (s, 2 H), 4.28 (s, 12 H), 8.31 (s, 4 H), 8.67 (s, 4 H),9.16 (s, 8 H).

[0148] 2.[5,10,15,20-Tetrakis(1-methylpyrazol-4-yl)porphyrinato]manganese(III)Chloride (50).

[0149] Porphyrin 49 (50 mg. 7.93×10⁻² mmol) was dissolved in DMF (10 mL)in a 25-mL round bottom flask equipped with a condenser. Manganese (II)chloride (150 mg, 1.19 mmol) was added and the reaction was heated at125° C. for 4 h. A stream of air was introduced and the reaction heatedfor an additional 2 h. The reaction was diluted with EtOAc (100 mL) andthe crude product was collected by vacuum filtration. Purification ofthe residue by column chromatography (10% MeOH/CH₂Cl₂) followed bycounterion exchange provided porphyrin 50 as a green solid (15 mg, 25%):mp>300° C.; UV-vis λ_(max)=471.0 nm, ε=9.55×10² L/cm-mol; API MS m/z=683[C₃₆H₂₈MnN₁₂]⁻.

[0150] 3. 5,10,15,20-Tetrakis(1,2-dimethylpyrazolium-4-yl)porphyrinTetrachloride (51).

[0151] Porphyrin 49 (200 mg, 0.32 mmol) was dissolved in DMF (15 mL) ina sealed tube reactor. Methyl iodide (2 mL, 32 mmol) was added and thesealed tube heated at 125° C. for 6 h. Dilution of the reaction mixturewith EtOAc resulted in the precipitation of crude product which wascollected by vacuum filtration and initially purified by columnchromatography (8:1:1 CH₃CN/water/saturated KNO

). Further purification by the double precipitation method providedporphyrin 51 as a dark purple solid (45 mg, 17%): ¹H NMR (300 MHz,DMSO-d₅l), δ −3.16 (s, 2 H), 4.55 (s, 24 H), 9.45 (s, 8 H), 9.50 (s, 8H).

[0152] 4.[5,10,15,20-Tetrakis(1,2-dimethylpyrazolium-4-yl)porphyrinato]manganese(III)Pentachloride (52).

[0153] Porphyrin 51 (40 mg, 4.30×10⁻² mmol) was dissolved in water (10mL). Manganese (II) chloride (90 mg. 0.72 mmol) was added and thereaction was heated at 50° C. Analysis of the reaction mixture by UV-visspectroscopy showed incomplete reaction. Additional MnCl₂ (210 mg, 1.67mmol) was added and heating of the reaction mixture was continued untilcompletion of reaction was indicated by UV-vis analysis. Filtrationfollowed by purification of the product by the double precipitationmethod provided porphyrin 52 (25 mg, 57%) as a brown solid: mp>300° C.:UV-vis λ_(max)=461.0 nm.

[0154] ε=7.82×10⁴ L/cm-mol: API MS m/z=683 [C₄₀H₄₀MnN₁₂-4CH₃]⁻.

[0155] XIV.[5,10,15,20-Tetrakis(1,3-dimethylimidazolium-5-yl)porphyrinato]manganese(III)Pentachloride (56).

[0156] 1. 5,10,15,20-Tetrakis(1-methylimidazol-5-yl)porphyrin (54).

[0157] To a refluxing solution of propionic acid (400 mL) and1-methylimidazole-5-carboxaldehyde (53, 2.0 g, 18.16 mmol), preparedaccording to literature procedure (Dener, J. M.; Zhang, L-H.; Rapoport,H. J. Org. Chem. 1993, 58, 1159-1166), was added pyrrole (1.26 mL, 18.16mmol). The reaction was covered with foil then heated under reflux for 5h. Upon cooling, the reaction mixture was exposed to air for 60 h. Thepropionic acid was then removed by vacuum distillation. The residue wasdissolved in 10% MeOH/CH₂Cl₂, then adsorbed onto silica gel (6 g).Purification by column chromatography (gradient elution, 5-10%MeOH/CH₂Cl₂) provided porphyrin 54 as a purple solid (600 mg, 21%): ¹HNMR (300 MHz. CDCl₃) δ −2.80,−2.75 ( s, 2 H. atropisomer NH). 3.42-3.58(multiple s, 12 H. atropisomer N—CH₃). 7.87-7.98 (multiple s. 4 H.atropisomer), 8.06 (s, 4 H), 8.95-8.99 (multiple s, 8 H. atropisomer).

[0158] 2. 5,10,15,20-Tetrakis(1,3-dimethylimidazolium-5-yl)porphyrinTetraiodide (55).

[0159] Porphyrin 54 (395 mg, 0.63 mmol) was dissolved in DMF (15 mL) ina sealed tube reactor. Methyl iodide (2 mL, 32 mmol) was added and thesealed cube was heated at 100° C. overnight. Dilution of the reactionmixture with EtOAc (200 mL) resulted in the precipitation of the crudeproduct which was collected by vacuum filtration. Purification by columnchromatography (8:1:1 CH₃CN/water/saturated KNO₃) provided porphyrin 55(250 mg, 33%) as a dark purple solid: ¹H NMR (300 MHz, DMSO-d₆) δ −3.25(s, 2 H), 3.46-3.64 (multiple s, 12 H, atropisomer), 4.30 (s, 12 H),8.68 (s, 4 H) 9.48 ( 8 H), 9.78 (s, 4 H).

[0160] 3.[5,10,15,20-Tetrakis(1,3-dimethylimidazolium-5-yl)porphyrinato]-manganese(III)Pentachloride (56).

[0161] Porphyrin 55 (200 mg, 0.17 mmol) was dissolved in methanol (100mL). Manganese (II) chloride (315 mg, 2.50 mmol) was added and an airstream introduced into the reaction mixture. The pH of the solution wasmaintained at 8 by the dropwise addition of 6N NaOH over the period ofthe reaction, after which time the pH was adjusted to 5 with 6N HCl. Thereaction was filtered on a fritted funnel. Purification of the productby the double precipitation method provided porphyrin 56 (63 mg, 41%) asa brown solid: mp>300° C.; UV-vis λ_(max)=454.0 nm, ε=1.23×10⁵L/cm-mmol.

[0162] XV.[5,15-Bis(fluorophenyl)-10,20-bis(1-methylimidazol-2-yl)porphyrinato]-manganese(III) Chloride (59) and[5,15-Bis(4-fluorophenyl)-10,20-bis(1,3-dimethylimidazolium-2-yl)porphyrinato]manganese(III)Trichloride (61).

[0163] 1.5,15-Bis(4-fluorophenyl)-10,20-bis(1-methylimidazol-2-yl)porphyrin (58).

[0164] In a foil-covered 1-L three-neck round bottom flask, equippedwith a magnetic stirrer and a N₂ outlet, was added dipyrromethane 25(1.00 g, 4.43 mmol), 4-fluoro-benzaldehyde (57, 550 mg, 4.43 mmol),sodium chloride (30 mg, 0.5 mmol) and CH₂Cl₂ (450 mL). The reactionmixture was stirred for 10 min, then TFA (2.0 mL, 26 mmol) was added.After a stirring period of 105 min. DDQ (1.51 g, 6.65 mmol) was added,and the mixture was stirred overnight. The solvent was removed by rotaryevaporation, and the crude residue was adsorbed onto silica gel (3 g).Purification by column chromatography (gradient elution, 5-10%MeOH/CH₂Cl₂) provided porphyrin 58 (229 mg, 16%) as a black solid: ¹HNMR (300 MHz, DMSO-d₅) δ −3.05 (s, 2 H), 3.70. 3.72 (2 s, 6 H,atropisomer N—CH₃), 7.73 (m, 8 H), 8.19 (s, 2 H), 8.30 (m 4 H), 9.02 (m,6 H): API-MS m/z=659 [C

0H₂₈F₂N₃

H]⁻.

[0165] 2.[5,15-Bis(4-fluorophenyl)-10,20-bis(1-methylimidazol-2-yl)porphyrinato]-manganese(III)Chloride (59).

[0166] Porphyrin 58 (85 mg, 0.13 mmol) was dissolved in DMF (7 mL) in a50-mL round bottom flask equipped with a condenser. Manganese (II)chloride (215 mg, 1.71 mmol) was added and the reaction was heated at120° C. for 3.5 h. The reaction was cooled to room temperature thenconcentrated by rotary evaporation. The crude residue was dissolved in20% MeOH/CH₂Cl₂ (100 mL) and adsorbed onto silica gel (2 g).Purification by column chromatography (gradient elution. 3-8%MeOH/CH₂Cl₂) provided porphyrin 59 as a green solid (15 mg, 16%):mp>300° C.: UV-vis λ_(max)=463.0 nm. ε=4.05×10⁴ L/cm-mol: API MS m/z=711[C₄₀H₂₆F₂MnN

]⁻.

[0167] 3.5,15-Bis(4-fluorophenyl)-10,20-bis(1,3-imidazolium-2-yl)porphyrinDichloride (60).

[0168] Porphyrin 58 (170 mg, 0.26 mmol) was dissolved in DMF (7 mL) in asealed tube reactor. Methyl iodide (6 mL, 96 mmol) was added and thesealed tube was heated at 100° C. overnight. The mixture was cooled toroom temperature and concentrated by rotary evaporation. The residue wasprecipitated as the chloride salt from acetone by the addition or Bu

NCl solution in acetone (0.3 g/mL). The solid was collected on a frittedfunnel, washed with copious quantities of acetone. and dried undervacuum at room temperature to provide porphyrin 60 as a dark purplesolid (196 mg). The product was used without further purification.

[0169] 4.[5,15-Bis(4-fluorophenyl)-10,20-bis(1,3-dimethylimidazolium-2-yl)porphyrinato]manganese(III)Trichloride (61).

[0170] Porphyrin 60 (196 mg, est. 0.26 mmol) dissolved in MeOH (30 mL)was slowly warmed to 55° C. then Mn(OAc)₃.2 H₂O (694 mg, 2.59 mmol) wasadded. After a stirring period of 3 h, the mixture was cooled to roomtemperature, filtered through Celite and concentrated by rotaryevaporation. The residue was purified by the double precipitation methodto provide porphyrin 61 (102 mg, 46% over two steps) as a dark greensolid: mp>300° C., UV-vis λ_(max)=458.0 nm: ε=1.30×10⁴ L/cm-mol; ES-MSm/z=967 [(C₄₂H₃₂F₂MnN₃)⁻³

2 (CF₃CO₂

)]⁻.

[0171] XVI.[5,10,15,20-Tetrakis(1,3-diethylimidazolium-2-yl)porphyrinato]manganese(III)Pentachloride (65).

[0172] 1. 5,10,15,20Tetrakis(1-ethylimidazol-2-yl)porphyrin (63).

[0173] To a refluxing solution of propionic acid (450 mL) and1-ethylimidazole-2-carboxaldehyde (62, 2.5 g, 20.0 mmol, prepared in asimilar manner as the methyl imidazole derivative 20) was added pyrrole(1.40 mL, 20.0 mmol). The reaction was covered in foil then heated underreflux for 5 h. Upon cooling, the reaction mixture was exposed to airovernight. The propionic acid was then removed by vacuum distillation.Repeated purification by column chromatography (gradient elution,CHCl₃/MeOH/concentrated NH₄OH/EtOAc) provided porphyrin 63 as a purplesolid (281 mg, 8.1%): ¹H NMR (300 MHz CDCl₃) δ −2.95, −2.90, −2.87 (3 s,2 H. atropisomer NH), 0.85-1.25 (multiple t. 12 H. atropisomer CH₃),3.61-3.88 (multiple q, 8 H, atropisomer CH₂), 7.55 (d 4 H), 7.70 (d, 4H), 8.98 (multiple s. 8 H, atropisomer).

[0174] 2. 5,10,15,20-Tetrakis(1,3-diethylimidazolium-2-yl)porphyrinTetraiodide (64).

[0175] Porphyrin 63 (106 mg, 0.15 mol) was dissolved in DMF (5 mL) in asealed tube reactor. Ethyl iodide (2.0 mL. 25 mmol) was added and thesealed tube was heated at 65° C. for 6 h. Dilution of the reactionmixture with EtOAc (100 mL) resulted in the precipitation of the crudeproduct which was collected by vacuum filtration, washed with chloroformand then purified by column chromatography (8:1:1 CH₃CN/water/saturatedKNO₃) to provide porphyrin 63 (140 mg, 69%) as a dark purple solid

¹NMR (300 MHz. DSMO-d₅) δ −3.22 (s, 2 H), 1.17 (t, 24 H), 4.01 (s, 16H), 8.70 (s, 8 H), 9.43 (s, 8 H).

[0176] 3.[5,10,15,20-Tetrakis(1,3-diethylimidazolium-2-yl)porphyrinato]-manganese(III)Pentachloride (65).

[0177] Porphyrin 64 (106 mg, 8.09×10⁻² mmol) was dissolved in methanol15 mL) then Mn(OAc)₃.2 H₂O (216 mg, 0.81 mmol) was added and thereaction heated at 55° C. for 2.5 h. The reaction was filtered throughcelite and then evaporated in vacuo. Purification of the product by thedouble precipitation method provided porphyrin 65 (65 mg, 78%) as abrown solid: mp>300° C., UV-vis λ_(max)=446.5 nm, ε=1.35×10⁵ L/cm-mol;ES-MS m/z=1307 [(C₄₈H₅₆MnN₁₂)⁻⁵

4(CF₃CO₂ ⁻)]⁻.

[0178] XVII.15,10,15,20Tetrakis(1-ethyl-3-methylimidazolium-2-yl)porphyrinato]-manganese(III)Pentachloride (67).

[0179] 1. 5,10,15,20-Tetrakis(1-ethyl-methylimidazolium-5-yl)porphyrinTetrachloride (66).

[0180] Porphyrin 21 (371 mg, 0.588 mmol) was dissolved in DMF (8 mL) ina sealed tube reactor. Ethyl iodide (7 mL, 88 mmol) was added and thesealed rube was heated at 60° C. overnight. The mixture was cooled toroom temperature and concentrated by rotary evaporation. The residue wasdissolved in water (20 mL) and purified by the double precipitationmethod to provide porphyrin 66 (349 mg, 67%) as a dark purple solid: ¹HNMR (300 MHz, DMSO-d₆) δ −3.23 (s, 2 H), 1.17 (m, 12 H), 3.77 (m, 12 H),4.03 (m, 8 H), 7.01, 7.18, 7.35 (multiple s, 8 H), 8.63 (d, 4 H), 9.36(s, 4 H).

[0181] 2.[5,10,15,20-Tetrakis(1-ethyl-3-methylimidazolium-2-yl)porphyrinato]-manganese(III)Pentachloride (67).

[0182] Porphyrin 66 (340 mg, 0.39 mmol) was dissolved in methanol (45mL) then Mn(OAc)₃.2 H₂O (680 mg, 2.53 mmol) was added, and the mixturewas stirred at 55° C. for 3.5 h. The mixture was cooled to roomtemperature, filtered through Celite (to remove insoluble solids), andconcentrated by rotary evaporation. The residue was purified by thedouble precipitation method to provide porphyrin 67 (324 mg, 85%) as abrown solid: mp>300° C.; UV-vis λ_(max)=446.5 nm; e=5.11×10⁴ L/cm-mol;ES-MS m/z=1251 [(C₄₄H₄₈MnN₁₂)⁺⁵+4 (CF₃CO₂ ⁻)]⁺.

EXAMPLE 2 Treatment of Bronchopulmonary Dysplasia Using Aeol-V (10123)

[0183] Neonatal baboons were delivered prematurely by Caesarian sectionand then treated either with 100% oxygen or only sufficient PRN FIO₂ tomaintain adequate arterial oxygenation. To establish the model, thirteen100% oxygen treated animals and seven PRN control animals were studied.Treatment with 100% oxygen results in extensive lung injury manifestedby days 9 or 10 of exposure and characterized by delayedalveolarization, lung parenchymal inflammation, and poor oxygenation.This is characteristic of the human disease, bronchopulmonary dysplasia,and is thought to be mediated, at least in part, by oxidative stress onthe developing neonatal lung. In a first trial of Aeol-V, a neonatalbaboon was delivered at 140 days gestation and placed in 100% oxygen.The animal received 0.25 mg/kg/24 hr given i.v. in a continuous infusionover the entire 10 day study period (see FIG. 2).

[0184] This animal showed marked improvement of the oxygenation index.There was no evidence of clinical decompensation of the lungs at days 9and 10. This suggests that Aeol-V can be used to treat oxidant stress inthe premature newborn.

[0185] All documents cited above are hereby incorporated in theirentirety by reference.

[0186] One skilled in the art will appreciate from a reading of thisdisclosure that various changes in form and detail can be made withoutdeparting from the true scope of the invention.

What is claimed is:
 1. A compound of formula

or pharmaceutically acceptable salt thereof. wherein R₁ and R₃ are thesame and are:

R₂ and R₄ are the same and are:

Y is halogen or —CO₂X, and X is the same or different and is an alkyland each R₅ is the same or different and is H or alkyl, wherein when R₁and R

are —H. R₂ and R

are not

. or when R₁ and R₃ are —H, and R₂ and R

are

, said compound is complexed with a metal selected from the groupconsisting of manganese, iron, copper, cobalt or nickel.
 2. The compoundaccording to claim 1 wherein R₁ and R

are the same and are:

R₂ and R₄ are the same and are:

Y is —F or —CO₂X, and X is the same or different and is a C₁₋₄ alkyl andeach R₅ is the same or different and is H or C₁₋₄ alkyl.
 3. The compoundaccording to claim 2 wherein X is methyl or ethyl.
 4. The compoundaccording to claim 1 wherein R₁, R₂, R₃ and R₄ are the same.
 5. Thecompound according to claim 1 wherein R₁, R₂, R₃ and R₄ are


6. The compound according to claim 5 wherein X is methyl or ethyl. 7.The compound according to claim 5 wherein R₁, R₂, R₃ and R₄ are thesame.
 8. The compound according to claim 7 wherein R₁, R₂, R₃ and R₄ are


9. The compound according to claim 1 wherein said compound is completedwith a metal selected from the group consisting of zinc, iron, nickel,cobalt, copper, manganese.
 10. The compound according to claim 9 whereinsaid compound is complexed with manganese.
 11. A method of protectingcells from oxidant-induced toxicity comprising contacting said cellswith a protective amount of a compound of formula

or pharmaceutically acceptable salt thereof, wherein R₁ and R₃ are thesame and are:

R₂ and R

are the same and are:

Y is halogen or —CO₂X, and X is the same or different and is an alkyland each R₅ is the same or different and is H or alkyl, so that saidprotection is effected.
 12. The method according to claim 11 whereinsaid compound is complexed with a metal selected from the groupconsisting of manganese, iron, copper, cobalt, nickel or zinc.
 13. Themethod according to claim 12 wherein said metal is manganese.
 14. Themethod according to claim 11 wherein said cells are mammalian cells. 15.The method according to claim 14 wherein said cells are cells of anisolated organ.
 16. The method according to claim 14 wherein said cellsare cells of an organ transplant.
 17. A method of treating a patientsuffering from a condition that results from or that is exacerbated byoxidant-induced toxicity comprising administering to said patient aneffective amount of a compound of formula

or pharmaceutically acceptable salt thereof, wherein R₁ and R

are the same and are:

R₂ and R₄ are the same and are:

Y is halogen or —CO₂X, and X is the same or different and is an alkyland each R₅ is the same or different and is H or alkyl, so that saidtreatment is effected.
 18. The method according to claim 17 wherein saidcompound is complexed with a metal selected from the group consisting ofmanganese, iron, copper, cobalt, nickel or zinc.
 19. The methodaccording to claim 18 wherein said compound is complexed with manganese.20. A method of treating a pathological condition of a patient resultingfrom degradation of NO

or a biologically active form thereof, comprising administering to saidpatient an effective amount of a compound of formula

or pharmaceutically acceptable salt thereof, wherein R₁ and R₃ are thesame and are:

R₂ and R₄ are the same and are:

Y is halogen or —CO₂X, and X is the same or different and is an alkyland each R₅ is the same or different and is H or alkyl, so that saidtreatment is effected.
 21. The method according to claim 20 wherein saidcompound is complexed with a metal selected from the group consisting ofmanganese, iron, copper, cobalt, nickel or zinc.
 22. The methodaccording to claim 21 wherein said compound is complexed with manganese.23. A method of treating a patient for an inflammatory diseasecomprising administering to said patient an effective amount of acompound of formula

or pharmaceutically acceptable salt thereof. wherein R₁ and R₃ are thesame and are:

R₂ and R₄ are the same and are:

Y is halogen or —CO₂X, and X is the same or different and is an alkyland each R₅ is the same or different and is H or alkyl, so that saidtreatment is effected.
 24. The method according to claim 23 wherein saidcompound is complexed with a metal selected from the group consisting ofmanganese, iron, copper, cobalt, nickel or zinc.
 25. The methodaccording to claim 24 wherein said compound is complexed with manganese.26. The method according to claim 23 wherein said inflammatory diseaseis an inflammatory lung disease.
 27. The method according to claim 26wherein said inflammatory lung disease is bronchopulmonary disease. 28.The method according to claim 26 wherein said inflammatory lung diseaseis asthma.
 29. The method according to claim 26 wherein saidinflammatory lung disease is pulmonary fibrosis.
 30. A method oftreating a patient for an ischemic reperfusion injury comprisingadministering to said patient an effective amount of a compound offormula

or pharmaceutically acceptable salt thereof. wherein R₁ and R₃ are thesame and are:

R₂ and R₄ are the same and are:

Y is halogen or —CO₂X, and X is the same or different and is an alkyland each R₅ is the same or different and is H or alkyl, so that saidtreatment is effected.
 31. The method according to claim 30 wherein saidcompound is complexed with a metal selected from the group consisting ofmanganese, iron, copper, cobalt, nickel or zinc.
 32. The methodaccording to claim 31 wherein said compound is complexed with manganese.33. The method according to claim 30 wherein said ischemic reperfusioninjury results from a stroke.